The goal of this project is to identify and to examine longitudinally, with positron emission tomography, the earliest alterations in cerebral physiology associated with the onsets of Alzheimer's disease and of parkinsonian dementia. PET determined measures of cerebral glucose metabolism, blood flow, muscarinic cholinergic receptor densities, and presynaptic cholinergic markers will be determined in cross-sectional studies of patients with early and late Alzheimer's disease, Parkinson's disease, with and without dementia, multiple infarct dementia, and controls. The same measures will be made and matched against measures of progressive cognitive decline in longitudinal studies of two groups of elderly subjects at high risk for the development of dementia, i.e., individuals with isolated memory impairment, and those with idiopathic Parkinson's disease who do not have dementia. The following hypotheses will be tested; 1) Parietal metabolic and perfusion decline is predictive of Alzheimer's disease in individuals with isolated memory impairment and is predictive of the onset of dementia in patients with idiopathic Parkinson's disease. 2) Presynaptic cholinergic deficits will distinguish early AD from other causes of isolated memory impairment, will distinguish among parkinsonian patients those destined to develop dementia, and will appear earlier and correlate better with cognitive decline than parietal hypo-metabolism. 3) Cortical muscarinic receptor binding patterns measured in vivo with PET are similar in early Alzheimer's disease and early parkinsonian dementia, but differ from post-mortem measures. To accomplish this, we will develop and refine several new PET techniques which are focused on measurement of neurotransmitter receptors, presynaptic uptake systems, and enzymes of transmitter metabolism. We will develop a new muscarinic receptor (MAChR) ligand, and acetylchol-inesterase (AChE) ligand, and a choline acetyltransferase (CAT) ligand. The development process includes preparation in positron emitter labeled form, evaluation in small animals and then in primates, development of mathematical models, and assessment of radiotracer pharmacokinetics in human PET studies. This project should develop important new information which is expected to aid the early differential diagnosis of dementing disorders and to provide new insights into the basic pathophysiology of these diseases. Such information could facilitate the introduction of knew treatment strategies.